Role of dyslipidemia in ischemic stroke patients treated in the telestroke network

PurposeThe relationship between the telestroke technology and clinical risk factors in a dysplipidemic ischemic stroke population and neurologic outcomes is not fully understood. This issue was investigated in this study.Patients and methodsWe analyzed retrospective data collected from a regional stroke registry to identify demographic and clinical risk factors in patients with improving (NIHSS ​≤ ​7) or worsening (NIHSS ​> ​7) neurologic outcome in dyslipidemic ischemic stroke population. We used logistic multivariate models to identify independent predictors of improving or worsening outcome based on dyslipidemia disease status in ischemic stroke patients.ResultsIn the adjusted analysis for dyslipidemic ischemic stroke population, cholesterol reducer use (odd ratio; [OR] ​= ​0.393, 95% confidence interval [CI], 0.176–0.879, P ​= ​0.023) and direct admission (OR ​= ​0.435, 95% CI, 0.199–0.953, P ​= ​0.037) were more likely to be associated with neurologic improvement and no clinical or demographic factors were associated with poor neurologic outcome in dyslipidemic ischemic stroke patients treated in the telestroke network.For the ischemic stroke population without dyslipidemia, increasing age (OR ​= ​1.070, 95% CI, 1.031–1.109, P ​< ​0.001), coronary artery disease (OR ​= ​3.633, 95% CI, 1.307–10.099, P ​= ​0.013), history of drug or alcohol abuse (OR ​= ​6.548, 95% CI, 1.106–38.777, P ​= ​0.038), and improvement in ambulatory outcome (OR ​= ​2.880, 95% CI, 1.183–7.010, P ​= ​0.020) were associated with worsening neurological functions, while being Caucasian (OR ​= ​0.294, 95% CI, 0.098–0.882, P ​= ​0.029) was associated with improving neurologic functions.ConclusionDemographic and clinical risk factors among the dysplipidemic ischemic stroke population in the telestroke network were not associated with worsening neurologic functions.     

Association of echocardiographic parameters with chest computed tomography score in patients with COVID-19 disease

PurposeAlthough coronavirus disease 2019 (COVID-19) primarily affects the pulmonary system, the involvement of the heart has become a well-known issue. Pulmonary CT plays an additive role in the diagnosis and prognosis of the disease. We aimed to investigate the association of echocardiographic indices with pulmonary CT scores and mortality in COVID-19 patients.Materials and methodsA total of 123 patients diagnosed with COVID-19 were included in this study. The British Society of Thoracic Imaging (BSTI) score and echocardiographic parameters were calculated, and echocardiographic indices were compared between BSTI score grades.ResultsDuring in-hospital follow-up, 36 of 123 patients (29.3%) had died. BSTI score, IVS, LVPWd, RV mid-diameter, RV basal diameter, RV longitudinal diameter, sPAP, and RVMPI were higher, and RVFAC, TAPSE, and RVS were lower in the non-survivor group than in the survivor group. There were statistically significant changes between BSTI scores in terms of LVPWd, RV mid diameter, RV basal diameter, RV longitudinal diameter, sPAP, RVFAC, RVMPI, and TAPSE. BSTI score was positively correlated with sPAP and RV basal diameter and negatively correlated with TAPSE and RVFAC. Multivariate logistic regression analysis demonstrated that sPAP (OR ​= ​1.071, p ​= ​0.002) and RV basal diameter (OR ​= ​1.184, p ​= ​0.005) were independent predictors of high BSTI scores (grade 4 and 5). Furthermore, age, sPAP, and a high BSTI score (grade 5) were independent predictors of in-hospital mortality in COVID-19 patients.ConclusionEchocardiographic indices were correlated with BSTI scores, and patients with higher BSTI scores had more cardiac involvement in COVID-19.     

Serum CK-MB,COVID-19 severity and mortality: An updated systematic review and meta-analysis with meta-regression

ObjectivesWe conducted a systematic review and meta-analysis with meta-regression of creatine kinase-MB (CK-MB), a biomarker of myocardial injury, in COVID-19 patients.MethodsWe searched PubMed, Web of Science and Scopus, for studies published between January 2020 and January 2021 that reported CK-MB, COVID-19 severity and mortality (PROSPERO registration number: CRD42021239657).ResultsFifty-five studies in 11,791 COVID-19 patients were included in the meta-analysis. The pooled results showed that CK-MB concentrations were significantly higher in patients with high disease severity or non-survivor status than patients with low severity or survivor status (standardized mean difference, SMD, 0.81, 95% CI 0.61 to 1.01, p<0.001). The rate of patients with CK-MB values above the normal range was also significantly higher in the former than the latter (60/350 vs 98/1,780; RR ​= ​2.84, 95%CI 1.89 to 4.27, p<0.001; I² ​= ​19.9, p ​= ​0.254). Extreme between-study heterogeneity was observed (I² ​= ​93.4%, p<0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified (effect size range, 0.77 to 0.84). Begg's (p ​= ​0.50) and Egger's (p ​= ​0.86) t-tests did not show publication bias. In meta-regression analysis, the SMD was significantly and positively associated with the white blood count, aspartate aminotransferase, myoglobin, troponin, brain natriuretic peptide, lactate dehydrogenase, and D-dimer.ConclusionsHigher CK-MB concentrations were significantly associated with severe disease and mortality in COVID-19 patients. This biomarker of myocardial injury might be useful for risk stratification in this group.     

INR and COVID-19 severity and mortality: A systematic review with meta-analysis and meta-regression

ObjectivesD-dimer elevations, suggesting a pro-thrombotic state and coagulopathy, predict adverse outcomes in coronavirus disease 2019 (COVID-19). However, the clinical significance of other coagulation markers, particularly the international normalized ratio (INR), is not well established. We conducted a systematic review and meta-analysis of the INR in COVID-19.MethodsA literature search was conducted in PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting INR values, measures of COVID-19 severity, and mortality (PROSPERO registration number: CRD42021241468).ResultsThirty-eight studies in 7440 COVID-19 patients with low disease severity or survivor status during follow up (50 ​% males, mean age 57 years) and 2331 with high severity or non-survivor status (60 ​% males, mean age 69 years) were identified. The INR was significantly prolonged in patients with severe disease or non-survivor status than in patients with mild disease or survivor status (standard mean difference, SMD, 0.60; 95 ​% confidence interval, CI 0.42 to 0.77; p ​< ​0.001). There was extreme between-study heterogeneity (I² ​= ​90.2 ​%; p ​< ​0.001). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. The Begg's and Egger's t-tests did not show publication bias. In meta-regression, the SMD of the INR was significantly associated with C-reactive protein (p ​= ​0.048) and D-dimer (p ​= ​0.001).ConclusionsProlonged INR values were significantly associated with COVID-19 severity and mortality. Both INR prolongation and D-dimer elevations can be useful in diagnosing COVID-19-associated coagulopathy and predicting clinical outcomes.     

Influence of narrow-band imaging (NBI) and enhanced operator’s attention during esophagus inspection on cervical inlet patches detection

PurposeHeterotopic gastric mucosa in the upper esophagus (cervical inlet patches - CIP) may be easily missed during esophagogastroduodenoscopy (EGD) due to low awareness of this usually, but not invariably, benign lesion. Narrow-band imaging (NBI) emphasizes contrast between normal esophageal mucosa and CIP. The purpose of this study was to investigate how NBI use and enhanced attention of operator during inspection of upper esophagus impacts cervical inlet patch detection rate (CIPDR).Materials and methodsThis is a prospective, randomized study in which we enrolled 1000 patients, qualified for diagnostic EGD. The trial was divided into two parts; the first, when 6 operators performed EGD with standard attention (SA), and the second, when the same operators were asked to step up with attention at CIP (enhanced attention - EA). In both parts of the study, patients were randomized to NBI and white light endoscopy (WLE) in 1:1 ratio. The study is registered in ClinicalTrials.gov (No. NCT03015571).ResultsDifferences in CIPDR between WLE and NBI in SA and EA were not statistically different (5.6% vs 7.6%; p ​= ​0.3, and 7.6% vs 11.6%; p ​= ​0.1, respectively). In multivariate regression analysis, the only factors improving CIPDR were NBI with EA (NBI_EA, OR 3.31; 95%CI 1.57–6.98; p ​= ​0.003) and sedation (OR 1.97; 95%CI 1.27–3.05; p ​= ​0.002).ConclusionsThe use of NBI combined with EA significantly improves CIPDR.     

Detection of EGFR mutations in liquid biopsy samples using allele-specific quantitative PCR: A comparative real-world evaluation of two popular diagnostic systems

PurposeThe detection of epidermal growth factor receptor (EGFR) mutations in plasma cell-free DNA (cfDNA) is an auxiliary tool for the molecular diagnosis of non-small cell lung cancer (NSCLC), especially when an adequate tumor tissue specimen cannot be obtained. We compared the diagnostic accuracy of two commonly used in vitro diagnostic-certified allele-specific quantitative PCR assays for detecting plasma cfDNA EGFR mutations.MethodsWe analyzed EGFR mutations in plasma cfDNA from 90 NSCLC patients (stages I–IV) before treatment (n ​= ​60) and after clinical progression on EGFR tyrosine kinase inhibitors (n ​= ​30) using the cobas EGFR mutation test v2 (Roche Molecular Systems, Inc.) and therascreen EGFR Plasma RGQ PCR kit (Qiagen GmbH).ResultsThere was higher concordance between plasma cfDNA and matched tumor tissue EGFR mutations with cobas (66.67%) compared with therascreen (55.93%). The concordance rate increased to 90.00% with cobas (Cohen's kappa coefficient, κ ​= ​0.80; p ​< ​0.0001) and 73.33% with therascreen (κ ​= ​0.49; p ​= ​0.0009) in advanced NSCLC patients. In treatment-naïve patients, cobas was superior to therascreen (sensitivity: 82.35% vs. 52.94%; specificity: 100% vs. 100%). In patients with clinical progression on EGFR tyrosine kinase inhibitors, EGFR exon 20 p.T790M was detected in 30% and 23% of cfDNA samples by cobas and therascreen, respectively.ConclusionsCobas was superior to therascreen for detection of plasma EGFR mutations in advanced NSCLC. Plasma cfDNA EGFR mutation analysis is complex; therefore, the diagnostic accuracy of commercially available assays should be validated.     

Multimodal longitudinal respiratory function assessment in very low birth weight 7-year-old children

PurposePreterm birth is associated with adverse pulmonary outcomes. We aimed to evaluate respiratory morbidities and lung function of very low birth weight (VLBW) Polish children followed up at the age of 7 years old, and to compare with electrical impedance segmentography (EIS) results recorded at 4 years of age.Materials and methodsVLBW children were compared with term controls using impulse oscillometry and spirometry. Perinatal data and current respiratory morbidities were analyzed and pulmonary function test results were compared with previous EIS results.ResultsWe included 40 VLBW children and 30 controls in the analysis. Elevated total airway resistance and forced expiratory volume in the first second below the lower limit of normal were more prevalent in VLBW children compared with term controls (15 vs 0%; 18 vs 0%). A positive bronchodilator response was more common in VLBW children (R_{5 Hz}: 46 vs 13.3%; R_{5–20 ​Hz}: 65 vs 36.7%). Children with bronchopulmonary dysplasia (BPD) had higher total airway resistance (R_{5 Hz}/R_{5 Hz pred}: 1.35 vs 0.95; p ​< ​0.001), large airway resistance (R_{20 Hz}/R_{20 Hz pred}: 0.89 vs 0.66; p ​= ​0.001), small airway resistance (R_{5–20 ​Hz}: 0.57 vs 0.34 ​kPa ​L⁻¹ ​s⁻¹; p ​= ​0.009), than controls. Strong correlation between BDR in EIS and R_{5 Hz}/R_{5 Hz pred} was observed in children with BPD (r ​= ​0.7).ConclusionVLBW school-aged children with BPD presented with substantial respiratory morbidity and persistent reduction of lung function, affecting small and large airways and lung parenchyma. EIS may be an alternative tool for lung function assessment in children with BPD.     

Metabolic mediators determine the association of antinuclear antibody subtypes with specific clinical symptoms in systemic sclerosis

PurposeThe aim of this study was to investigate the possible link between different types of systemic sclerosis-specific antinuclear antibodies, adipokines and endothelial molecules which were recently found to have a pathogenic significance in systemic sclerosis.Materials/methodsSerum concentration of adiponectin, resistin, leptin, endothelin-1, fractalkine and galectin-3 were determined in the sera of patients with systemic sclerosis (n ​= ​100) and healthy controls (n ​= ​20) using ELISA.ResultsThe following associations between antinuclear antibodies and increased serum concentrations were identified: anticentromere antibodies with endothelin-1 (p ​< ​0.0001; mean level in patients 2.21 vs control group 1.31 ​pg/ml), anti-topoisomerase I antibodies with fractalkine (p ​< ​0.0001; 3.68 vs 1.68 ​ng/ml) and galectin-3 (p ​= ​0.0010, 6.39 vs 3.26 ​ng/ml). Anti-RNA polymerase III antibodies were associated with increased resistin (p ​< ​0.0001; 15.13 vs 8.54 ​ng/ml) and decreased adiponectin (p ​< ​0.0001; 2894 vs 8847 ​ng/ml).ConclusionIn systemic sclerosis metabolic and vascular factors may serve as mediators between immunological abnormalities and non-immune driven clinical symptoms.     

Prognostic value of late gadolinium enhancement mass index in patients with pulmonary arterial hypertension

PurposeDysfunction of the right ventricle (RV) is an important determinant of survival in patients with pulmonary arterial hypertension (PAH). The presence of late gadolinium enhancement (LGE) in cardiac magnetic resonance (CMR) at RV insertion points (RVIPs) has been found in majority of PAH patients and was associated with parameters of RV dysfunction. We hypothesize, that more detailed quantification of LGE may provide additional prognostic information.Material and methodsTwenty-eight stable PAH patients (mean age 49.9 ​± ​15.9 years) and 12 healthy subjects (control group, 44.8 ​± ​13.5 years) were enrolled into the study. Septal LGE mass was quantified at the RVIPs and subsequently indexed by subject’s body surface area. Mean follow-up time of this study was 16.6 ​± ​7.5 months and the clinical end-point (CEP) was defined as death or clinical deterioration.ResultsMedian LGE mass index (LGEMI) at the RVIPs was 2.75 ​g/m2 [1.41–4.85]. We observed statistically significant correlations between LGEMI and hemodynamic parameters obtained from right heart catheterization – mPAP (r ​= ​0.61, p ​= ​0.001); PVR (r ​= ​0.52, p ​= ​0.007) and from CMR – RVEF (r ​= ​−0.54, p ​= ​0.005); RV global longitudinal strain (r ​= ​0.42, p ​= ​0.03). Patients who had CEP (n ​= ​16) had a significantly higher LGEMI (4.49 [2.75–6.17] vs 1.67 [0.74–2.7], p ​= ​0.01); univariate Cox analysis confirmed prognostic value of LGEMI. Furthermore, PAH patients with LGEMI higher than median had worse prognosis in Kaplan-Meier analysis (log-rank test, p ​= ​0.0006).ConclusionsThe body surface indexed mass of LGE at RV septal insertion points are suggestive of RV hemodynamic dysfunction and could be a useful non-invasive marker of PAH prognosis.     

Retrospective analysis of clinical and pathomorphological features of lupus nephritis in children

PurposeThe aim of the study was to evaluate the clinical course and pathomorphological correlations in Polish children with the diagnosis of lupus nephritis (LN).MethodsWe retrospectively analyzed the medical records of 39 children hospitalized due to LN in 7 pediatric nephrology units in Poland between 2010 and 2019. Demographic data, clinical symptoms at the onset of LN and laboratory parameters were reviewed. We analyzed Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), histological LN findings with the activity (IA) and chronicity index (IC).ResultsWe examined 32 girls and 7 boys, median age at LN onset was 14.75 (IQR 13.0–16.0) years, SLEDAI of 22.0 (IQR 18.0–27.0) points; LN histological class: IV (59.4%), III (18.9%), III/V (10.8%), IV/V (8.1%), VI (2.7%); IA 8.0 (IQR 6.0–11.0) points, IC 1.05 (IQR 0–2.0) points.Children with nephrotic (n ​= ​22) and non-nephrotic (n ​= ​17) proteinuria differed in median Hb level (9.55, IQR 8.3–11.2 vs 10.9, IQR 10.1–11.6 ​g/L; P ​< ​0.05), albumin level (2.5, IQR 2.1–3.19 vs 3.6, IQR 3.4–4.1 ​g/dL; P ​< ​0.001), proteinuria (5.76, IQR 3.0–7.5 vs 1.08, IQR 0.53–1.50 ​g/day; P ​< ​0.0001), eGFR (53.9, IQR 27.0–68.8 vs 96.7, IQR 73.8–106.2 ​mL/min/1.73 ​m²; P ​< ​0.01) and occurrence of hypertension (77% vs 23%; P ​< ​0.01).In multivariate analysis Hb level (β ​= ​8.0; 95%CI, 1.90–14.11) was the significant predictor of eGFR<90 ​mL/min/1.73 ​m².ConclusionsProliferative forms of LN in children may have a varying clinical presentation.Children with LN with nephrotic range proteinuria have lower Hb level, lower eGFR and higher occurrence of hypertension. Hb level is the significant predictor of eGFR<90 ​mL/min/1.73 ​m² in children with LN.     

Blood reelin in the progression of chronic liver disease

PurposeReelin is an extracellular matrix protein originally found to be associated with neuropsychiatric disorders. Recent findings indicate, that reelin may also play an important role in the process of liver fibrosis as well as in the development of hepatocellular carcinoma (HCC). Against this background, the aim of our study was to explore alterations in blood reelin levels in different stages of chronic liver diseases.Patients and methodsWe analyzed blood samples of patients with chronic liver disease without liver fibrosis (n ​= ​25), with liver fibrosis (n ​= ​36), with liver cirrhosis (n ​= ​74), with HCC (n ​= ​26) as well as of healthy controls (n ​= ​15). Blood reelin concentrations were determined utilizing an enzyme-linked immunosorbent assay.ResultsBlood reelin levels were significantly elevated in patients who had liver fibrosis or cirrhosis compared to patients without liver fibrosis and healthy controls (13.9 (10.2–21.1) ng/ml vs. 11.2 (8.8–16.8) ng/ml, p ​= ​0.032). Importantly, patients with HCC displayed significantly higher reelin concentrations compared to patients with liver cirrhosis alone (27.0 (17.3–35.9) ng/ml vs. 16.6 (11.0–22.7) ng/ml, p ​< ​0.001). Blood reelin was not relevantly linked to liver function, inflammation and etiology of liver disease.ConclusionsOur results demonstrate, that blood reelin levels are altered in different stages of chronic liver disease, which makes reelin a potential biomarker in this setting. This may be especially relevant with regard to its use as an additional tumor marker of HCC.     

Higher rate of aortic stenosis progression in patients with bicuspid versus tricuspid aortic valve – A single center experience

PurposeWe sought to investigate aortic stenosis (AS) progression rate (pr) with the comparison between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) morphology.Materials and methodsWe compared ASpr in patients with BAV and TAV examined by transthoracic echocardiography (TTE) in the years 2004–2019.ResultsData from 363 TTEs in 161 AS patients (median age 70 [61–77] years; 63% men; 25% with BAV; 20% with severe AS) performed at different time points (median time interval 10 months) was analyzed. We assessed changes of AS severity with peak velocity through aortic valve (Vmax), mean/peak pressure gradients (MG/PG), aortic valve area by planimetry and continuity equation (AVAce). We compared pr (defined as parameter change per year) between the BAV and the TAV groups. BAV patients showed faster ASpr with odds ratio 3.467 and 95% confidence intervals 1.36 to 8.86, moreover, expressed as a quicker AVAce decrease 0 (−0.4-0.0) in the BAV vs. 0 (−0.15 – 0.0) cm²/year in the TAV group, p ​= ​0.02. Furthermore, in BAV, female sex was associated with lower ASpr (p ​= ​0.01), and in the whole group a larger aortic diameter was a predictor of faster progression (p ​< ​0.001).ConclusionThe ASpr, expressed as a decrease in the AVAce, was faster in BAV. Moreover, ASpr depends on both: valve morphology being faster in BAV and Vmax increase. Furthermore, the female sex was related to slower pace of AVA reduction in BAV subgroup whereas the larger baseline aortic diameter associated to faster AS progression in the whole studied group.     

Expression levels of serum circulating microRNAs in pediatric patients with ventricular and supraventricular arrhythmias

PurposeAberrant expression of various miRNA species has been implicated in numerous cardiac diseases, e.g., heart failure, hypertrophy, conduction disturbances, and arrhythmogenesis. The aim of this study was to determine whether miR-1, miR-133a, and miR-133b can serve as biomarkers in the diagnosis of ventricular (Va) and supraventricular (SVa) arrhythmias in pediatric patients.Materials and methodsMolecular analysis included 30 patients with SVa or Va (13–17.5 years; 14 boys/16 girls) and 20 non-arrhythmic controls. Arrhythmia was confirmed by 24-h Holter ECG recording. miRNA was extracted from serum using the miRNeasy^R Serum/Plasma Kit. miScript SYBR Green PCR Kit (Qiagen) was used to quantify miRNA expression.ResultsThe levels of miR-1 and miR-133a expression were significantly higher in the SVa group than in the controls (p ​= ​0.0327 and p<0.0001, respectively). Additionally, both groups of patients with arrhythmia presented significantly lower expression levels of miR-133b than the controls (p<0.01 for both comparisons). The level of miR-133a expression in the SVa group was significantly higher than in the Va group (p ​= ​0.0124). ROC analysis demonstrated that the expressions of miR-1 and miR-133a could differentiate between the SVa patients and arrhythmia-free controls (AUC ​= ​0.7091, p ​= ​0.07 and AUC ​= ​0.8021, p ​= ​0.007, respectively). Furthermore, the expression of miR-133b was shown to distinguish patients with SVa and Va from the arrhythmia-free controls (AUC ​= ​0.7273, p ​= ​0.07 and AUC ​= ​0.8030, p ​= ​0.04, respectively).ConclusionsmiR-1, miR-133a, and miR-133b have the potential to become diagnostic biomarkers of arrhythmia in pediatric patients.     

The significance of HOXB7 and IL17RB serum levels in prognosis of hormonally dependent breast cancer: A pilot study

PurposeImproved prognostication of a patient's outcome could allow for personalized treatment decisions in breast cancer. Homeobox B7 (HOXB7) and interleukin 17 receptor B (IL17RB) are proteins reportedly involved in the development of hormonal therapy resistance. Their prognostic value was previously investigated in tumor tissue but recent mass spectrometric detection of HOXB7 and IL17RB proteins in serum has prompted us to perform the first prognostic evaluation of their serum levels.Patients and methodsThe study included 81 premenopausal breast cancer patients that received adjuvant hormonal therapy. The median follow-up period was 61 months. HOXB7 and IL17RB serum protein levels were measured by quantitative sandwich ELISA and prognostically evaluated by Cox proportional hazards regression analysis.ResultsHOXB7 protein was detected in 96.3% and IL17RB in 33.3% of serum samples. Higher levels of serum HOXB7 significantly associated with favorable disease outcome by prognosticating distant (by HR ​= ​0.04; P ​= ​0.001) and local recurrence (by HR ​= ​0.03, P ​= ​0.001). The recurrence rates in the HOXB7^high and HOXB7^low subgroups of patients (cut-off 81.5 ​pg/mL) were 0% and 17%, respectively. Serum IL17RB levels did not significantly associate with either local or distant events. The multivariate analysis highlighted estrogen receptor, histological grade, nodal status and HOXB7 as independent prognostic parameters.ConclusionsOur findings validate the previous mass-spectrometry data by showing that HOXB7 and IL17RB cellular proteins are detectable in serum by a standard ELISA assay. Furthermore, we show that HOXB7 serum levels are the relevant prognosticator of response to hormonal therapy.     

Vitamin D and risk of ankylosing spondylitis: A two-sample mendelian randomization study

ObjectivesTo study whether Vitamin D levels are causally associated with ankylosing spondylitis (AS).MethodsTwo-sample Mendelian randomization (TSMR) analysis was performed by employing MR-Egger regression, weighted median (WM¹), inverse-variance weighted (IVW), and weight mode (WM²) methods. The odds ratio (OR) with 95% confidence intervals (CIs) was used to evaluate this association.ResultsThe results of IVW show that no causal association between vitamin D and AS (OR = 0.999, 95%CI = 0.997, 1.002, P = 0.724). The MR-Egger regression results show that genetic pleiotropy does not bias the results (intercept = ?4.474E-05, SE = 2.830E-05, P = 0.255). The MR-Egger method no supported causal association between vitamin D and AS (OR = 1.000, 95%CI = 0.996, 1.005, P = 0.879). WM¹ (OR = 1.002, 95%CI = 0.999, 1.005, P = 0.837) and WM² (OR = 0.998, 95%CI = 0.996, 1.002, P = 0.910) approach also not found a causal relationship between vitamin D levels and AS. The significant heterogeneity was not observed by Cochran's Q test. The “leave-one-out” analysis also proved lack of a single SNP affected the robustness of our results.ConclusionBased on our analysis, there is lack of a strong evidence to support a causal inverse association between vitamin D levels and ankylosing spondylitis.     

Tocilizumab versus baricitinib in hospitalized patients with severe COVID-19: an open label,randomized controlled trial

ObjectiveRandomized controlled trials comparing tocilizumab and baricitinib in patients with coronavirus disease 2019 (COVID-19) are needed. This was an open-label, randomized controlled trial aiming to address this unmet need.MethodsTo determine whether baricitinib was non-inferior to tocilizumab, we assessed whether the upper boundary of the two-sided 95% CI of the hazard ratio (HR) did not exceed 1.50. The primary outcome was mechanical ventilation or death by day 28. Secondary outcomes included time to hospital discharge by day 28 and change in WHO progression scale at day 10.ResultsWe assigned 251 patients with COVID-19 and a PaO_2/FiO₂ ratio of <200 to receive either tocilizumab (n = 126) or baricitinib (n = 125) plus standard of care. Baricitinib was non-inferior to tocilizumab for the primary composite outcome of mechanical ventilation or death by day 28 (mechanical ventilation or death for patients who received baricitinib, 39.2% [n = 49/125]; mechanical ventilation or death for patients who received tocilizumab, 44.4% [n = 56/126]; HR, 0.83; 95% CI, 0.56–1.21; p 0.001 for non-inferiority). Baricitinib was non-inferior to tocilizumab for the time to hospital discharge within 28 days (patients who received baricitinib- discharged alive: 58.4% [n = 73/125] vs. patients who received tocilizumab- discharged alive: 52.4% [n = 66/126]; HR, 0.85; 95% CI, 0.61–1.18; p < 0.001 for non-inferiority). There was no significant difference between the baricitinib and tocilizumab arms in the change in WHO scale at day 10 (0.0 [95% CI, 0.0–0.0] vs. 0.0 [95% CI, 0.0–1.0]; p 0.83).DiscussionIn the setting of this trial, baricitinib was non-inferior to tocilizumab with regards to the composite outcome of mechanical ventilation or death by day 28 and the time to discharge by day 28 in patients with severe COVID-19.     

Genotype-phenotype associations in a large PTEN Hamartoma Tumor Syndrome (PHTS) patient cohort

BackgroundPathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.MethodsInformation was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.ResultsAt time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5–3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1–2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1–3.5), with trends up to 2–4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3–0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4–0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.ConclusionThe PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.     

Three-year clinical and optical coherence tomography follow-up after stereotactic radiotherapy for neovascular age-related macular degeneration

PurposeThe long-term clinical outcome of adjuvant stereotactic radiotherapy (SRT) in neovascular age-related macular degeneration (nAMD) patients was evaluated.MethodsThis case-control study included patients with unilateral nAMD, who underwent SRT complementary to standard anti-VEGF treatment. Only patients with monthly follow-up over at least three years were considered. Number of intravitreal injections, visual acuity (VA), central retinal thickness (CRT), and subfoveal choroidal thickness (SFCT) were evaluated and compared to baseline as well as to an age- and gender-matched control group, who received anti-VEGF monotherapy.ResultsTwenty patients were irradiated and had complete follow-up. Cumulatively, SRT patients needed significantly less injections than non-irradiated ones over three years (14 vs. 18, p ​= ​0.014), while median VA did not show statistically significant changes (0.4 logMAR at baseline to 0.65 logMAR at final follow-up, p ​= ​0.061). CRT remained steady, but SFCT showed a continuous thinning of almost 50 ​μm (p ​= ​0.031) in irradiated patients over three years. Multiple linear regression analysis revealed that SFCT and VA at time of irradiation are significant prognostic factors of VA change in SRT patients over the following three years (F(2,17) ​= ​23.946, p<0.001, R² of 0.738).ConclusionsSRT significantly reduced the cumulative anti-VEGF treatment burden over three years, however, this was mainly driven by the results of the first year after irradiation. A thinner SFCT at time of irradiation was associated with poorer visual outcome. While further research and investigation are warranted to elucidate the underlying pathogenesis, SFCT could be a potential biomarker when evaluating a patient’s suitability for SRT.     

Risk factors of complications during noninvasive mechanical ventilation -assisted flexible bronchoscopy

PurposeFlexible bronchoscopy (FB) causes airway narrowing and may cause respiratory failure (RF). Noninvasive mechanical ventilation (NIV) is used to treat RF. Until recently, little was known about noninvasive mechanical ventilation assisted flexible bronchoscopy (NIV-FB) risk and complications.Materials and methodsA retrospective analysis of NIV-FB performed in 20 consecutive months (July 1, 2018–February 29, 2020) was performed. Indications for: FB and NIV, as well as impact of comorbidities, blood gas results, pulmonary function test results and sedation depth, were analyzed to reveal NIV-FB risk. Out of a total of 713 FBs, NIV-FB was performed in 50 patients with multiple comorbidities, acute or chronic RF, substantial tracheal narrowing, or after previously unsuccessful FB attempt.ResultsIn three cases, reversible complications were observed. Additionally, due to the severity of underlining disease, two patients were transferred to the ICU where they passed away after >48h. In a single variable analysis, PaO₂ 69 ​± ​18.5 and 49 ​± ​9.0 [mmHg] (p ​< ​0.05) and white blood count (WBC) 10.0 ​± ​4.81 and 14.4 ​± ​3.10 (p ​< ​0.05) were found predictive for complications. Left heart disease indicated unfavorable NIV-FB outcome (p ​= ​0.046).ConclusionsNIV-FB is safe in severely ill patients, however procedure-related risk should be further defined and verified in prospective studies.